Aging causes deterioration of various aspects of physiology in normal adults, including memory performance. Such age related declines in cognitive performance have long been recognized by medical practitioners. Plato and Aristotle (384-322 BC) both wrote about the declines in mental performance with age, and how this should be used to exclude aged individuals from certain jobs: “there is not much left of the acumen of the mind which helped them in their youth, nor of the faculties which served the intellect, and which some call judgment, imagination, power of reasoning and memory. They see them gradually blunted by deterioration and see that they can hardly fulfill their function.”
In more recent times, mental decline has been quantified by a series of cognitive tests and is now a well accepted phenomenon. Impairment of memory performance in the elderly has been detected in several standard memory tests, including the Wechsler Memory Scale (WMS) and immediate and delayed Visual Reproduction Test (Trahan et al. Neuropsychology, 1988 19(3) p. 173-89), the Rey Auditory Verbal Learning Test (RAVLT) (Ivnik, R. J. et al. Psychological Assessment: A Journal of Consulting and Clinical Psychology, 1990 (2): p. 304-312) and others (for review see Larrabee and Crook, Int. Psychogeriatr, 1994 6(1): p. 95-104.
To characterize memory loss more systematically, the National Institute of Mental Health (NIMH) created a work group which proposed a criteria for “age-associated memory impairment” (AAMI) (Crook T. H. et al. Dev. Neuropsychol, 1986, 2: p. 261-276.) The criteria for AAMI include, complaints of memory loss in persons over the age of 50 years, impairment on a standardized memory test compared to young adults, and absence of dementia or any medical condition that could produce cognitive deterioration. Because AAMI is related to “normal” aging and not a pathological condition the prevalence is expected to be high and increase with increasing age. Recent estimates vary from 18% to 85%, depending on the subjects' age and the population studied.
The clinical course and causes of AAMI are poorly understood. Since AAMI is a part of aging it has frequently been attributed to the general deterioration of the body due to cellular damage. Age related increases in cellular damage are often ascribed to oxidative damage from a variety of sources. Despite being part of normal aging, several possible treatments strategies have been attempted to alleviate AAMI and have met with some success. For example, phosphatidylserine has shown some efficacy in AAMI trials.
The human brain is one of the most metabolically active organs in the body and requires large amounts of energy for proper function. Cerebral oxygen consumption for an average adult human is roughly 3.5 ml/100 g/min. For an average sized brain of 1,400 grams, this is about 40 ml O2/min. At rest the average person will use ˜250 ml O2/min. Therefore the brain uses approximately 16 percent of the total O2 consumed. This is remarkable in that the brain accounts for only about 2 percent of the total body mass. Most of the oxygen in the brain is used for the oxidation of glucose. Under normal conditions glucose is primary fuel for the brain while the contribution of fatty acids is considered minor. The average adult brain consumes approximately 110 grams of glucose a day. The dependence on glucose puts the brain at risk if circulating glucose levels drop, such that sudden bouts of hypoglycemia cause impairment of cognitive function. For example, if large amounts of insulin are injected this will cause a sudden drop in blood glucose and cognitive dysfunction, including memory problems, sensory disturbances and even coma.
However under certain conditions when glucose levels are limiting, such as neonatal development or starvation, the liver will mobilize ketone bodies as a supplemental fuel for the body, and in particular cerebral neurons. Ketone bodies (β-hydroxybutyrate, acetoacetate and acetone) are derived from the incomplete oxidation of fatty acids by both hepatocytes and glial cells, and released into the bloodstream to provide a supplement to glucose. Ketone bodies cannot fully substitute for glucose, but can account for a significant fraction of cerebral metabolism. In early studies conducted on fasting of obese human subjects, considerable uptake of ketone bodies into the brain was observed. The uptake was sufficiently large to account for almost 50% of total cerebral O2 usage.
The ability of ketone bodies to supplement glucose in the brain has been used to treat conditions of low glucose availability to the brain. GLUT1 is a constitutive glucose transporter that transports glucose into the central nervous system (CNS). The high glucose requirement of the brain requires that two functional copies of the GLUT1 gene be present. If one copy of GLUT1 is non-functional this results in GLUT1 deficiency syndrome. The resulting low glucose levels during development lead to infant seizures, delayed development and microcephaly. Partial relief of these symptoms can be achieved by increasing serum ketone levels by administration of a ketogenic diet. Thus, if glucose uptake or use is limited, ketone bodies may serve to supplement energy requirements.
One physiological hallmark of aging in mammals is a decreased uptake and metabolism of glucose within the brain. The impaired glucose metabolism in the brain may contribute or exacerbate the cognitive deficits observed during normal aging. Facilitation of memory in elderly subjects occurs when glucose levels are elevated by the administration of carbohydrate. However, such a treatment poses challenges since elevated blood glucose levels are difficult to maintain and must be within a relatively narrow window, as excessive hyperglycemia is associated with cognitive impairments. Therefore it is important to explore other aspects of the model.
Substantial scientific evidence has shown that defects in cerebral glucose metabolism occur during aging in several mammalian species. A series of studies done in the 1980s demonstrated decreased cerebral glucose metabolism in aged rats. One study examined the role that the decreased metabolic rate played in the cognitive decline of aging rats. Aged (22-24 months) and young (3 month) rats were tested in a series of behavioral tests including: water maze test (spatial learning), time on a round bridge (motor coordination), open field test (spontaneous activity) and the startle response. Cerebral glucose utilization was also examined in these same rats. As a group, aged animals demonstrated lowered regional glucose utilization when compared with the younger animals. The aged group also showed large heterogeneity in extent and regions of decreased glucose metabolism. Interestingly, the amount of decreased regional glucose metabolism correlated with impairment in cognitive tests. For example, declines in glucose use in the prefrontal cortex correlated well with spatial learning impairment. Similar decreases in glucose metabolism have been observed in rhesus monkeys and dogs.
Early studies in humans using positron emission tomography failed to find evidence of decreased cerebral glucose metabolism in normal aged subjects. However, more recent studies employing more sensitive techniques and instrumentation have found that regional decreases in glucose metabolism are associated with normal human aging. In a study of 25 healthy volunteers between the ages of 20 to 68, total oxygen consumption in the brain was found to be reduced approximately 6% per decade. Importantly, the decline still was evident when cortical atrophy was included in the calculations, demonstrating that the decreases in metabolism are not simply due to cell loss. Others have mapped the decreases in metabolism to specific regions of the brain to create a “metabolic topography of normal aging”. This map located metabolic decline to largely frontal regions of the brain and represented an approximately 12% decrease in global metabolic rate between the ages of 20 and 80.
Attempts to improve memory performance in the elderly by increasing glucose availability have met with some success in both animal models and in humans. For example, in a Y maze test, both young and old mice normally enter the new arm if there is no delay when the animals are placed in the maze. This is a measure of spontaneous alteration. If, however, a delay of 1 minute is used, young mice (2 month) still perform well on this task but old mice (2 year) do not. Yet, if the mice are given glucose before the test, the old mice perform as well as the young mice, and there is no increase in the ability of the young mice (Stone, W. S., et al., Glucose attenuation of deficits in spontaneous alternation behavior and augmentation of relative brain 2-deoxyglucose uptake in old and scopolamine-treated mice, Psychobiology, 1992, 20:270-279). This is consistent with studies in humans that have largely shown increases in cognition following glucose administration in elderly groups but not for young groups. In one study, two sets of subjects, one young (mean age 20 years old) and one elderly (mean age 67 years old) were given either a sugar free lemon drink sweetened with artificial sweeteners (0 g carbohydrates) or a drink sweetened with sugar (50 g carbohydrate) on alternate visits in a crossover design. On each visit the subjects were given a series of cognitive tests, including a paired association task, a test of contextual memory, a test of immediate recall, and a test of visual memory. The glucose improved the scores of the elderly group but not the young group. Such experiments have been replicated several times and seem to indicate that memory facilitation by glucose is characterized by an inverted-U shape, with too much glucose negating the effect.
The mechanism for increased memory after glucose administration is still unclear but may be related to increased energy production and the corresponding increased acetylcholine production. Yet, glucose may not be a practical means to elevate memory in the aged for several reasons. (1) Elevated glucose levels are difficult to maintain in a healthy mammal. (2) Hyperglycemia may improve memory but may prove detrimental to other organ systems. (3) Elevated blood glucose may lead to chronically elevated insulin levels and the problems associated with hyperinsulinemia.
Interestingly other substrates may also facilitate memory in aged animals. For example, morphine is known to impair memory formation yet this effect can be blocked by co-administering glucose. Similarly pyruvate can also block the effects of morphine administration.
There has been long experience with ketogenic diets, which mimic starvation, in children treated for epilepsy. The diet is a medical therapy and should be used under the careful supervision of a physician and/or dietician. The diet carefully controls caloric input and requires that the child eat only what has been included in the calculations to provide 90% of the day's calories as fats. However, such diets are generally unsuitable for use in adults due to: (1) adverse effects on the circulatory system from incorporation of cholesterol and long chain triglycerides as the primary fat in these diets; (2) poor patient compliance due to the unappealing nature of the low carbohydrate diet.
The prior art provides descriptions of ketogenic diets in which fat is high and carbohydrates are limited. In summary, the rationale of such diets is that intake of high amounts of fat, whether long-chain or medium-chain triglycerides can increase blood ketone levels in the context of a highly-regimented diet in which carbohydrate levels are absent or limited. Limitation of carbohydrate and insulin are believed to prevent re-esterification in adipose tissue. Although the ketogenic diet has been known for decades, there does not appear to be any prior art teaching or suggesting that MCT therapy be used to treat diseases of reduced neuronal metabolism in patients with any age-associated cognitive decline, such as AAMI, and the like.
There is thus a need in the art to develop compositions and methods for the treatment and/or prevention of cognitive impairment, particularly in aging or geriatric mammals such as humans.
Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Full citations for publications not cited fully within the specification are set forth at the end of the specification.